¥6,600,000 (Direct Cost : ¥6,600,000)

The present study was designed to investigate the application of basic fibroblast growth factor (bFGF) to restoration of ischemic cerebral damage. The investigators proposed research projects such as expression of bFGF mRNA and immediate early genes (IEGs) after the cerebral ischemia, and the neuroprotective effects of bFGF to ameliorate infarction volume. The following results were obtained. (1)EXPRESSION OF bFGF GENE AFTER TRANSIENT FOCAL ISCHEMIA : bFGF mRNA was markedly expressed in the peri-infarct cortex and caudoputamen during 6-48 hr after the reperfusion, and disappeared by 5 days. The expression of bFGF was also observed in the remote areas such as bilateral hippocampus and cingulate cortex. Signals of bFGF mRNA focused on neurons and glial cells. Previous reports showed that bFGF receptor mRNA was upregulated in the peri-infarct areas. Intrinsic bFGF released from the damaged tissue could influence the healing response through the auto-paracrine manner. Because IEGs preceded
… More the bFGF mRNA expression, IEGs might regulate the bFGF transcription (Iwata A et al.J Neurotrauma 1997). (2)THE EFFECTS OF INTRAVENOUS bFGF ADMINISTRATION ON THE INFARCT SIZE : Permanent focal ischemia was made in rats. Thirty min after the initiation of ischemia, human recombinant bFGF was given intravenously for 3 days using osmotic minipumps. Infarct volumes in the rats treated with bFGF were significantly smaller than in the saline treated controls. Dose-dependency was present within 0.4 to 2 mug/kg/hr. Infarct volume increased at the dose of 10 mug/kg/h, probably as a result of hypotension. The reduction of infarction size was obvious in cortex rather than in caudate-putamen. Our study confirmed that long-term and low-dose intravenous administration of bFGF was potentially neuroprotective against focal ischemia without systemic side effects. (3)ONGOING PROJECT : The investigation of behavioral and physiological effects are in progress.1.ラット局所脳虚血再灌流モデルを用いin situ hybridization法で検討した結果,bFGF遺伝子は虚血後6時間から2-3日にわたり虚血境界領域の大脳皮質や基底核ばかりでなく,両側海馬,cingulate gyrusなど広範な領域に出現することがわかった.また遺伝子誘導は神経細胞にとどまらずグリア細胞にも認められた.bFGFが虚血負荷後の神経細胞の生存維持や修復機転に広く関わることが示唆された(Iwata et al.1997 J Neurotrauma).またbFGFが発現する領域は,アポトーシスが生じる部位と一致し,アポトーシスによる虚血病巣拡大の防止にbFGFが深く関わることを裏付けた.2,ラット局所脳虚血作成後,浸透圧ポンプを用いてbFGFの3日間持続静脈内投与を行い,虚血病巣の縮小効果および至適容量の決定を試みた.虚血細胞は,0.4〜2μg/kg/hの間で容量依存性に縮小し,生理的パラメーターには異常を認めなかった.10μg/kg/hでは逆に虚血巣拡大を示し,血圧低下が悪影響を及ぼしたと考えられた.容量依存性を示したデータは過去に報告はなく新たな知見である.持続注入法はbFGFの血圧降下作用を軽減し,大容量を注入することができ,有効な方法であることが判明した.今後の展開として,外因性bFGFの脳内分布,行動生理学的効果の判定,他の神経栄養因子発現へ及ぼす影響を検討し,bFGF臨床応用に向けての基礎データとする. Less